Polymeric topical compositions

ABSTRACT

The present invention relates to topical antibacterial compositions. The compositions comprise an antibacterial agent such as mupirocin, water, a polymer and a volatile solvent present in an amount of less than about 40%. The invention also relates to methods of treatment by administering the compositions to a patient in need thereof, and to the use of such compositions in the treatment of bacterial conditions.

FIELD OF THE INVENTION

The present invention relates to topical antibacterial compositions.

BACKGROUND OF THE INVENTION

Bactroban® (2% mupirocin) ointment and Bactroban® (2% calcium mupirocin)cream and ointment are marketed by GlaxoSmithKline for the treatment offuruncle, impetigo and wounds that have become infected.

U.S. Pat. No. 5,082,656 (Hui et al.) describes an antibacterialcomposition for topical administration comprising: from about 0.5% toabout 10% of an antibacterial compound, from about 1% to about 30% of anon water soluble polymeric composition, from about 0.5% to about 40% ofa plasticizer, and from about 50% to about 95% of a solvent (such asethanol or isopropanol). Upon topical application of the antibacterialcomposition, the solvent will evaporate and leave a thin protective filmof polymeric composition which retains the antibacterial compoundagainst the skin.

U.S. Pat. No. 6,211,250 (Tomlinson et al.) describes topicalcompositions comprising at least one rate modulating polymer, a volatilesolvent and at least one physiologically active agent. Tomlinsondiscloses compositions comprising a hydrophilic polymer and ahydrophobic polymer selected to modulate the rate of release of theactive agent. The compositions comprise greater than 50% volatilesolvent. A high level of volatile solvent is desirable in as much as itwill solubilize the hydrophobic polymer and evaporate to leave apolymeric film on the surface of the skin. However, a high level ofvolatile solvent has the potential disadvantage of irritating the skin,particularly on open wounds or lesions.

U.S. Pat. No. 6,582,683 (Jezior) describes a dermal barrier compositionwhich comprises water, a hydrophilic polymer emulsion and a hydrophobicpolymer emulsion. The dermal barrier composition is moisture activated,and remains inert until the hydrophobic and hydrophilic polymeremulsions contact a suitable substrate such as human skin. The dermalbarrier composition is itself an emulsion, and may contain a biocidalagent for treatment of a skin disorder or condition. The dermal barriercomposition may also contain other active agents such as sunscreens,insect repellents and fungicides. The composition does not contain avolatile solvent.

US Published Application No. 2005/0175641 (Deo et al.) describes topicalcompositions comprising at least one physiologically active agent, avolatile solvent, and ethyl cellulose as a hydrophobic polymer, alongwith a hydrophilic polymer. The volatile solvent is present in an amountof greater than 50% by weight.

U.S. Pat. No. 7,678,366 (Friedman et al.) describes a therapeutic nailvarnish comprising a pharmaceutically active agent, a humectant, water,less than about 7.5% by weight of a polymeric film forming agent, atleast one additional excipient, and a solvent system including at leastone volatile solvent. Friedman et al. discloses pharmaceutically activeagents which are antifungal agents, such as naftifine or terbinafine.The nail varnish may further comprise a second active ingredient, suchas clobetasol.

There remains a need in the art for topical preparations that are ableto deliver an active agent, particularly an antibacterial, to thesurface of the skin in a controlled manner and without irritation.Furthermore, it is desirable that such a preparation would becosmetically elegant, and rapidly dry after topical application to leavea film on the surface of the skin. The present invention is believed toaddress these unmet needs.

SUMMARY OF THE INVENTION

According to an embodiment, the present invention provides a topicalpharmaceutical composition comprising an antibacterial agent, a polymer,water and less than about 40% volatile solvent.

According to another embodiment the present invention provides for amethod of treating a disease, disorder or condition of the skin, in amammal in need thereof, the method comprises administering to saidmammal, preferably a human subject, a topical pharmaceutical compositioncomprising an antibacterial agent, a polymer, water and less than about40% volatile solvent.

According to a further embodiment, the invention relates to the use of atopical pharmaceutical composition comprising an antibacterial agent, apolymer, water and less than about 40% volatile solvent, in thepreparation of a medicament for the treatment of a disease, disorder orcondition of the skin.

In another embodiment, the invention relates to the use of a topicalpharmaceutical composition comprising an antibacterial agent, a polymer,water and less than about 40% volatile solvent, in the treatment of adisease, disorder or condition of the skin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates modulation of the rate of release of calciummupirocin where different variants of PVP/VA are used, i.e. PVP/VA 60:40(), PVP/VA 70:30 (♦) and PVP/VA 30:70 (▪).

FIG. 2 illustrates modulation of the rate of release of calciummupirocin (first order derivative) where different variants of PVP/VAare used, i.e. PVP/VA 60:40 (), PVP/VA 70:30 (♦) and PVP/VA 30:70 (▪).

FIG. 3 illustrates the rate constant (k) and release exponent (n) inconnection with release of calcium mupirocin from compositionscomprising different variants of PVP/VA, i.e. PVP/VA 60:40, PVP/VA 70:30and PVP/VA 30:70.

FIGS. 4 a-4 c illustrates the rub and water resistance of thecompositions of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for a topical pharmaceutical compositioncomprising an antibacterial agent, a polymer, water and less than about40% volatile solvent, and optionally additional dermatologicallyacceptable excipients.

Exemplary antibacterial agents include, but are not limited to,mupirocin, gentamicin, neomycin, streptomycin, cefpodoxime proxetil,clindamycin, lincomycin, erythromycin, bacitracin, gramicidin(s),vancomycin, doxycycline, minocycline, oxytetracycline, tetracycline,fosfomycin, fusidic acid, sulfacetamide, metronidazole, benzoyl peroxideand dapsone, pharmaceutically acceptable salts thereof, and mixturesthereof.

Suitably, the antibacterial agent is present in the composition in atherapeutically effective amount. In an embodiment, the antibacterialagent is present in an amount from about 0.1% to about 10% by weight.

In one embodiment, the antibacterial agent is selected from the groupconsisting of mupirocin, clindamycin, metronidazole and pharmaceuticallyacceptable salts thereof. In a particular embodiment, the antibacterialagent is mupirocin or a salt thereof. In an embodiment, the mupirocin ora salt thereof is calcium mupirocin. In one embodiment, the mupirocin ora salt thereof is sodium mupirocin. In one embodiment, the mupirocin ora salt thereof is calcium mupirocin. In another embodiment, the calciummupirocin is present either as an amorphous or crystalline form. Inanother embodiment, the mupirocin or a salt thereof is mupirocin (thefree acid). In yet another embodiment, the mupirocin or a salt thereofis a mixture of calcium mupirocin and mupirocin (the free acid).Suitably, the calcium mupirocin and mupirocin in such an embodiment arepresent in a ratio of about 1:3 to about 3:1, suitably about 1:1.

The benefit of combining calcium mupirocin and mupirocin (the free acid)in a single composition according to the present invention is that therespective forms of mupirocin will be released from the topicalcomposition at different rates, so as to facilitate a combination ofrapid release and more sustained release of the active agent. Thesediffering release rates arise from the differenthydrophilicity/hydrophobicity of calcium mupirocin and mupirocin (thefree acid). The same would be present for sodium mupirocin and mupirocin(free acid), as well potentially as other salt forms of mupirocin withthe free acid.

In an embodiment, the mupirocin or a salt thereof is present in anamount from about 0.1% to about 10% by weight. Suitably, the mupirocinor a salt thereof is present in an amount from about 1% to about 3% byweight, such as about 1%, 2% or 3% by weight, for example. In aparticular embodiment, the mupirocin or a salt thereof is present in anamount of about 2% by weight.

In an alternative embodiment, the antibacterial agent is clindamycin ora salt thereof. Suitably, the clindamycin or a salt thereof isclindamycin phosphate or clindamycin hydrochloride. In an embodiment,the clindamycin or a salt thereof is clindamycin phosphate. In a furtherembodiment, the clindamycin or a salt thereof is present in an amountfrom about 0.5% to about 2% by weight, such as about 1% by weight.

In another embodiment, the antibacterial agent is metronidazole.Suitably, the metronidazole is present in an amount from about 0.1% toabout 2% by weight. In a particular embodiment, the metronidazole ispresent in an amount of about 1% by weight.

Polymer

In an embodiment, the polymer present in the formulation is a copolymer.

Suitably, the copolymer is polyvinylpyrrolidone-vinyl acetate copolymer,also known as PVP/VA. In one embodiment, the ratio of PVP monomer to VAmonomer in the PVP/VA copolymer is from about 30:70 to about 70:30. Inanother embodiment, the ratio of PVP monomer to VA monomer is about30:70. In another embodiment, the ratio of PVP monomer to VA monomer isabout 60:40. In yet another embodiment, the ratio of PVP monomer to VAmonomer is about 70:30. While there are many suppliers of PVP/VA, manyratios are available from 70:30 to 20:80 are available under thetradename Luviskol, produced by BASF.

Hydrophobic polymers are either insoluble in low ethanolic formulations(≦20% ethanol) or precipitate out of the formulation due to interactionswith the hydrophilic drug. Hydrophilic homopolymers (such ashydroxypropylcellulose (HPC)) form thermodynamically stableformulations, but tend to give rise to a burst release of a hydrophilicdrug. A difference in drug release has been observed when thehydrophobicity of the copolymer PVP/VA is modified by changing the ratioof PVP (hydrophilic moiety) to VA (hydrophobic moiety) as will befurther described herein in the Methods Section. A hydrophilic polymer(e.g. a carbomer and PVP/VA (60:40)) has also been shown to reduce thedrug release of a lipophilic drug as compared to the hydrophilic drug.

In an embodiment, the polymer is present in the composition in an amountfrom about 1% to about 60% by weight. In one embodiment, the polymer ispresent in an amount from about 5% to about 30% by weight, such as about10% by weight. In another embodiment, the polymer is present in anamount from about 30% to about 60% by weight, such as from about 45% toabout 55% by weight, or about 50% by weight.

Water

In an embodiment, the composition comprises water in an amount fromabout 20% to about 85% by weight. In one embodiment, the compositioncomprises water in an amount from about 40% to about 85% by weight. Inanother embodiment the composition comprises from about 50% to about 70%by weight. In another embodiment, the composition comprises water in anamount from about 20% to about 40% by weight.

Volatile Solvent

In an embodiment, the volatile solvent is an organic solvent. Theorganic solvent is suitably selected from ethanol, propanol,iso-propanol, n-butyl alcohol, t-butyl alcohol, butoxy ethanol, acetone,ethyl acetate or butyl acetate, and mixtures thereof. In one embodimentthe at least one volatile solvent present in the composition is ethanol.

In another embodiment, the volatile solvent is a mixture of at least twovolatile solvents. Suitably the combination contains ethanol as thefirst solvent in combination with a second solvent. Suitably, the secondsolvent is propanol, iso-propanol, n-butyl alcohol, t-butyl alcohol,butoxy ethanol, acetone, ethyl acetate or butyl acetate. In anembodiment, the volatile solvent is a mixture of ethanol andiso-propanol. In another embodiment, the volatile solvent is a mixtureof ethanol and ethyl acetate.

In an embodiment, the volatile solvent is present in an amount of lessthan about 40% by weight. In one embodiment, the volatile solvent ispresent in an amount from about 5% to about 30% by weight. In anotherembodiment, the volatile solvent is present in an amount from about 10%to about 25% by weight.

Suitably, the ratio of volatile solvent to water in the topicalpharmaceutical composition is from about 1:1 to about 1:10. In oneembodiment, the ratio of volatile solvent to water in the topicalpharmaceutical composition is from about 1:1 to about 1:3. In anembodiment, the ratio of volatile solvent to water in the topicalpharmaceutical composition is from about 1:1.25 to about 1:2. In anotherembodiment the ratio is about 1:1.65.

Second Pharmaceutically Active Agent

According to an embodiment, the topical pharmaceutical composition maycomprise a second pharmaceutically acceptable active agent.

In one embodiment, the second pharmaceutically active agent is selectedfrom the group consisting of a second antibacterial agent, a retinoid, acorticosteroid, an antifungal agent, a skin conditioning agent, anutritional agent, and an antiseptic agent. Suitably, the secondpharmaceutically active agent is present in an amount in the compositionfrom about 0.001% to about 20% by weight, depending on the nature of thesecond active agent.

Exemplary antibacterial agents suitable for use as the secondantibacterial agent include, but are not limited to, gentamicin,neomycin, streptomycin, cefpodoxime proxetil, clindamycin, lincomycin,erythromycin, bacitracin, gramicidin(s), vancomycin, doxycycline,minocycline, oxytetracycline, tetracycline, fosfomycin, fusidic acid,sulfacetamide, metronidazole, benzoyl peroxide and dapsone, saltsthereof, and mixtures thereof. Suitably, the second antibacterial agentis present in an amount from about 0.1% to about 10% by weight.

Exemplary retinoids include, but are not limited to, tazarotene,tretinoin, isotretinoin, acitretin, etretinate, adapalene, bexarotene,alitretinoin, retinol, retinal, retinyl palmitate, retinyl acetate,retinyl propionate, retinyl linoleate, ethyl5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate,6-(2-4,4-dimethylthiochroman-6-yl)-ethynyl)-3-pyridylmethanol,6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)pyridine-3-carbaldehyde,pharmaceutically acceptable salts thereof, and mixtures thereof.Suitably, the retinoid is present in an amount from about 0.01% to about1% by weight.

In an embodiment, the retinoid is selected from the group consisting oftretinoin, tazarotene and adapalene. In one embodiment, the retinoid istretinoin. In another embodiment, the retinoid is tazarotene. In yetanother embodiment, the retinoid is adapalene.

Exemplary corticosteroids include, but are not limited to, alclometasonedipropionate, amcinonide, beclomethasone dipropionate, betamethasonebenzoate, betamethasone dipropionate, betamethasone valerate,budesonide, clobetasol propionate, clobetasone butyrate, cortisoneacetate, desonide, desoximetasone, diflorasone diacetate, diflucortolonevalerate, fluclorolone acetonide, flumethasone pivalate, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone, fluprednideneacetate, flurandrenolide, flurandrenolone, fluticasone propionate,halcinonide, halobetasol propionate, hydrocortisone, hydrocortisoneacetate, hydrocortisone butyrate, hydrocortisone propionate,hydrocortisone valerate, methylprednisolone acetate, mometasone furoate,pramoxine hydrochloride, prednisone acetate, prednisone valerate,triamcinolone acetonide, prednicarbate, salts thereof, and mixturesthereof. Suitably, the corticosteroid is present in an amount from about0.01% to about 2% by weight.

Exemplary antifungal agents include, but are not limited to, thoseselected from the group consisting of echinocandins such asanidulafunin, caspofungin and micafungin; polyenes such as amphotericinB, candicidin, filipin, fungichromin, hachimycin, hamycin, lucensomycin,mepartricin, natamycin, nystatin, pecilocin, perimycin; allylamines suchas butenafine, naftifine and terbinafine; imidazoles such as bifonazole,butoconazole, chlormidazole, cloconazole, clotrimazole, econazole,enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole,lanoconazole, miconazole, neticonazole, omoconazole, oxiconazolenitrate, sertaconazole, sulconazole and tioconazole; thiocarbamates suchas liranaftate, tolciclate, tolindate and tolnafate; triazoles such asalbaconazole, pramiconazole, fluconazole, itraconazole, posaconazole,ravuconazole, saperconazole, terconazole and voriconazole; and otherantifungal agents such as acrisorcin, amorolfine, biphenamine,bromosalicylchloranilide, buclosamide, calcium propionate,chlorphenesin, ciclopirox, cloxyquin, coparaffinate, exalamide,flucytosine, haloprogin, hexetidine, loflucarban, nifuratel, potassiumiodide, propionic acid, pyrithione, salicylanilide, sodium propionate,sulbentine, tenonitrozole, triacetin, undecylenic acid, zinc propionate,griseofulvin, oligomycins, pyrroInitrin, siccanin, viridian,pharmaceutically acceptable salts thereof, and mixtures thereof.Suitably, the antifungal agent is present in an amount from about 0.1%to about 5% by weight.

Exemplary skin-conditioning agents include, but are not limited to,hydrocarbon oils and waxes, silicones, fatty acid derivatives,cholesterol, di- and tri-glycerides, vegetable oils, acetoglycerideesters, alkyl esters, alkenyl esters, lanolin, milk tri-glycerides, waxesters, beeswax, sterols, phospholipids, hyaluronic acid,pharmaceutically acceptable salts thereof, and mixtures thereof. In anembodiment, the skin-conditioning agent is hyaluronic acid or a saltthereof, such as sodium hyaluronate. Suitably, the skin conditioningagent is present in an amount from about 0.1% to about 20% by weight.

Exemplary nutritional agents include vitamins such as vitamins A, B, C,D, E and K and prodrugs thereof, essential amino acids, essential fats,antioxidants, pharmaceutically acceptable salts thereof, and mixturesthereof. Suitably, the nutritional agent is present in an amount fromabout 0.01% to about 2% by weight.

Exemplary antiseptics include, but are not limited to, hydrogenperoxide, chlorhexidine, cetrimide, povidone iodine, silversulfadiazine, triclosan, pharmaceutically acceptable salts thereof, andmixtures thereof.

In another embodiment, the first antibacterial agent is mupirocin or apharmaceutically acceptable salt thereof and the second pharmaceuticallyactive agent is a second antibacterial agent. Suitably, the firstantibacterial agent is mupirocin, sodium or calcium mupirocin or amixture thereof. In one embodiment the first antibacterial agent iscalcium mupirocin. In one embodiment, the second antibacterial agent ismetronidazole. In another embodiment the first antibacterial agent iscalcium mupirocin and the second antibacterial agent is metronidazole.

In another embodiment, the antibacterial agent is mupirocin or apharmaceutically acceptable salt thereof and the second pharmaceuticallyactive agent is a retinoid. Suitably, the antibacterial agent ismupirocin, sodium or calcium mupirocin or a mixture thereof. In oneembodiment the antibacterial agent is calcium mupirocin. In oneembodiment the retinoid is tretinoin. In another embodiment, retinoid isadapalene. In one embodiment the antibacterial agent is calciummupirocin and the retinoid is tretinoin or adapalene.

In another embodiment, the antibacterial agent is mupirocin or apharmaceutically acceptable salt thereof and the second pharmaceuticallyactive agent is a corticosteroid. Suitably, the antibacterial agent ismupirocin, sodium or calcium mupirocin or a mixture thereof. In oneembodiment the antibacterial agent is calcium mupirocin. In oneembodiment, corticosteroid is clobetasol propionate. In anotherembodiment, corticosteroid is hydrocortisone or an ester thereof. In oneembodiment the antibacterial agent is calcium mupirocin and theantibacterial agent is clobetasol propionate or hydrocortisone or anester thereof.

In another embodiment, the antibacterial agent is mupirocin or apharmaceutically acceptable salt thereof and the second pharmaceuticallyactive agent is an antifungal agent. Suitably, the antibacterial agentis mupirocin, sodium or calcium mupirocin or a mixture thereof. In oneembodiment the antibacterial agent is calcium mupirocin. In oneembodiment, the antibacterial agent is calcium mupirocin and theantifungal agent is clotrimazole.

In another embodiment, the antibacterial agent is mupirocin or apharmaceutically acceptable salt thereof and the second pharmaceuticallyactive agent is a skin conditioning agent. Suitably, the mupirocin orpharmaceutically acceptable salt thereof is calcium mupirocin.

In another embodiment, the antibacterial agent is mupirocin or apharmaceutically acceptable salt thereof and the second pharmaceuticallyactive agent is an antiseptic agent. Suitably, the mupirocin orpharmaceutically acceptable salt thereof is calcium mupirocin.

Dermatologically Acceptable Excipients

In an embodiment, the present topical pharmaceutical compositionsfurther comprise one or more dermatologically acceptable excipients.

Suitably, the excipient is selected from the group consisting of aco-solvent, a pH adjusting agent, a humectant, a film extender, achelating agent, an antioxidant, a preservative, a gelling agent, afragrance, a colorant, a penetration enhancer, or a combination ormixture thereof.

In one embodiment, the present compositions are formulated as asolution, gel, serum, aerosol spray or aerosol foam. Suitably, thecomposition is formulated as a solution. In another embodiment, thecomposition is formulated as a gel.

Co-Solvent

The topical pharmaceutical compositions may further comprise aco-solvent. The function of the co-solvent is to further solubilise(i.e. in conjunction with the volatile solvent) the active agent and/orthe polymer in the composition.

Exemplary co-solvents include, but are not limited to, alcohols such asamyl alcohol, benzyl alcohol, cyclohexanedimethanol, diacetone alcohol,hexyl alcohol, tetrahydrofurfuryl alcohol; carboxylic acids such asacetic acid or multi carboxylic acid derivatives; diols such as1,2-hexanediol, butylene glycol, diethylene glycol, dipropylene glycol,ethyl hexanediol, ethylene glycol, hexylene glycol, pentylene glycol,propylene glycol, tetraethylene glycol, triethylene glycol, tripropyleneglycol; and polyols such as polyethylene glycol, butanetriol, glyceroland 1,2,6-hexanetriol.

In one embodiment, the co-solvent is propylene glycol. In anotherembodiment, the co-solvent is hexylene glycol. In yet anotherembodiment, the co-solvent is a mixture of at least two co-solvents. Inan embodiment, the co-solvent is a mixture of polyethylene glycol andpropylene glycol.

In one embodiment, the co-solvent is present in the composition in anamount of from about 1% to about 30% by weight. In another embodiment,the co-solvent is present in an amount of from about 1% to about 10% byweight. In yet another embodiment, the co-solvent is present in anamount of from about 15% to about 25% by weight.

In an alternative embodiment, the topical pharmaceutical composition isdevoid or substantially devoid of co-solvent. In one embodiment, thetopical pharmaceutical composition is devoid of co-solvent. In anotherembodiment, the topical pharmaceutical composition is substantiallydevoid of co-solvent.

In another embodiment, the topical pharmaceutical composition comprisesa volatile solvent in an amount from about 10% to about 25% by weightand is substantially devoid of a co-solvent. In yet another embodiment,the topical pharmaceutical composition comprises a volatile solvent inan amount from about 10% to about 25% by weight, and is devoid ofco-solvent.

pH Adjusting Agent

The topical pharmaceutical compositions may further comprise a pHadjusting agent. In one embodiment, the pH adjusting agent is a base.Suitable bases include amines, bicarbonates, carbonates, and hydroxidessuch as alkali or alkaline earth metal hydroxides, as well as transitionmetal hydroxides. In an embodiment, the base is sodium hydroxide orpotassium hydroxide.

In another embodiment, the pH adjusting agent is an acid, an acid salt,or mixtures thereof. Suitably, the acid is selected from the groupconsisting of lactic acid, acetic acid, maleic acid, succinic acid,citric acid, phosphoric acid, nitric acid, sulphuric acid andhydrochloric acid.

In yet another embodiment, the pH adjusting agent is a buffer. Suitably,the buffer is selected from the group consisting of citrate/citric acid,acetate/acetic acid, phosphate/phosphoric acid, propionate/propionicacid, lactate/lactic acid, carbonate/carbonic acid, ammonium/ammonia andedetate/edetic acid, or a combination or mixture thereof. In oneembodiment, the pH adjusting agent is citrate/citric acid.

In one embodiment, the pH adjusting agent is present in an amount fromabout 0.01% to about 10% by weight. In another embodiment, the pHadjusting agent is present in an amount sufficient to adjust the pH ofthe composition to between about 4 to about 9. Suitably, the compositionis adjusted to a pH between about 4 to about 6.5, or a pH between about6.5 to about 9.

Humectant

The topical pharmaceutical compositions may further comprise ahumectant.

Exemplary humectants include, but are not limited to, glycerol,sorbitol, maltitol, polydextrose, triacetin, propylene glycol,polyethylene glycol (PEG) esters including PEG-20 stearate, PEG-40stearate, PEG-150 stearate, PEG-150 distearate and PEG-100 stearate,alkoxylated alcohols including laureth-12, ceteareth-20, laureth-23,glycereth-7, glycereth-12, glycereth-26, PEG-4, PEG-6, PEG-8, PEG-12,PEG-32, PEG-75, PEG-150, or a combination or mixture thereof. In anembodiment, the humectant is glycerol.

In one embodiment, the present compositions comprise about 0.1% to about10% by weight of a humectant. In another embodiment, the compositionscomprise about 0.5% to about 5% by weight of a humectant.

Film Extenders

The present topical pharmaceutical compositions may further comprise afilm extender. Exemplary film extenders include, but are not limited to,calcium carbonate, calcium phosphate, calcium stearate, magnesiumstearate, zinc stearate, calcium sulfate, colloidal silicon dioxide,kaolin, magnesium carbonate, magnesium silicate, sodium stearylfumarate, talc, titanium dioxide, zinc oxide, or a combination ormixture thereof.

Suitably, the film extender is present in an amount from about 0.1% toabout 2% by weight.

Chelating Agents

The present topical pharmaceutical compositions may further comprise achelating agent. Exemplary chelating agents include, but are not limitedto, citric acid, isopropyl (mono) citrate, stearyl citrate, lecithincitrate, gluconic acid, tartaric acid, oxalic acid, phosphoric acid,sodium tetrapyrophosphate, potassium monophosphate, sodiumhexametaphosphate, calcium hexametaphosphate, sorbitol, glycine(aminoacetic acid), methyl glucamine, triethanolamine (trolamine),ethylene diamine tetraacetic acid (EDTA), dihydroxyethylglycine (DEG),diethylene triamine pentaacetic acid (DPTA), nitrilotriacetic acid(NTA), N-(hydroxyethyl)-ethylenetriaminetriacetic acid (HEDTA),aminocarboxylates, dimercaperol (BAL), larixinic acid (maltol),unidentate ligands (fluoride and cyanide ions), diphenylthiocarbazone,o-phenanthroline, barium diphenylamine sulfonate, sodium glucoheptonate,8-hydroxyquinoline, olefin complexes (such as dicyclopentadienyl iron),porphyrins, phosphonates, or a combination or mixture thereof.

In one embodiment, the chelating agent is EDTA.

Suitably, the chelating agent is present in an amount from about 0.1% toabout 1% by weight.

Antioxidants

The present topical pharmaceutical compositions may further comprise anantioxidant. Exemplary antioxidants include, but are not limited to,butylated hydroxytoluene (BHT), butylated hydroxyanisole, tocopherol,propyl gallate, vitamin E TPGS, or a combination or mixture thereof.

Suitably, the present compositions comprise an antioxidant in an amountfrom about 0.001% to about 1% by weight.

Preservatives

The present topical pharmaceutical compositions may further comprise apreservative. Exemplary preservatives include, but are not limited to,benzyl alcohol, diazolidinyl urea, methyl paraben, ethyl paraben, propylparaben, butyl paraben, phenoxyethanol, sorbic acid, benzoic acid, saltsthereof, or a combination or mixture thereof. In one embodiment, thepreservative is benzyl alcohol. In another embodiment, the preservativeis phenoxyethanol.

Suitably, the present compositions comprise a preservative in an amountfrom about 0.01% to about 2% by weight.

Gelling Agent

The present topical pharmaceutical compositions may further comprise agelling agent. Exemplary gelling agents include, but are not limited to,agar, alginate, arabinoxylan, carrageenan, carboxymethylcellulose,hydroxypropyl methylcellulose, cellulose, curdlan, gelatin, gellan,β-glucan, tragacanth gum, guar gum, gum arabic, locust bean gum, pectin,starch, a carbomer, acrylate copolymers, silica, xanthan gum, saltsthereof, or a combination or mixture thereof.

In one embodiment, the gelling agent is xanthan gum. In anotherembodiment, the gelling agent is a carbomer. In another embodiment, thegelling agent is a mixture of at least two gelling agents.

Suitably, the gelling agent is present in the composition in an amountfrom about 0.1% to about 2% by weight.

In one embodiment, the invention provides a topical pharmaceuticalcomposition comprising:

(a) calcium mupirocin,

(b) a polymer in an amount from about 30% to about 60% by weight,

(c) water in an amount from about 20% to about 40% by weight, and

(d) a volatile solvent in an amount from about 10% to about 25% byweight.

In another embodiment, the invention provides a topical pharmaceuticalcomposition comprising:

(a) calcium mupirocin,

(b) a polymer in an amount from about 30% to about 60% by weight,

(c) water in an amount from about 20% to about 40% by weight,

(d) a volatile solvent in an amount from about 10% to about 25% byweight, and

(e) a gelling agent.

In yet another embodiment, the invention provides a topicalpharmaceutical composition comprising:

(a) calcium mupirocin,

(b) a polymer in an amount from about 30% to about 60% by weight,

(c) water in an amount from about 20% to about 40% by weight, and

(d) a volatile solvent in an amount from about 10% to about 25% byweight, and

-   -   wherein the composition is devoid or substantially devoid of        co-solvent.

In another embodiment, the invention provides a topical pharmaceuticalcomposition comprising:

(a) calcium mupirocin,

(b) a polymer in an amount from about 30% to about 60% by weight,

(c) water in an amount from about 20% to about 40% by weight,

(d) a volatile solvent in an amount from about 10% to about 25% byweight, and

(e) a gelling agent, and

-   -   wherein the composition is devoid or substantially devoid of        co-solvent.

Suitably, the polymer in any of the above 4 formulations is PVP/VA. Inone embodiment, the ratio of PVP monomer to VA monomer in the PVP/VA isfrom about 30:70 to about 70:30. In a particular embodiment, the ratioof PVP monomer to VA monomer is about 30:70. In another embodiment, theratio of PVP monomer to VA monomer is about 60:40. In yet anotherembodiment, the ratio of PVP monomer to VA monomer is about 70:30.

Suitably, the calcium mupirocin is present in an amount from about 1% toabout 3% by weight. In one embodiment, the calcium mupirocin is presentin an amount from about 2% by weight.

In another embodiment, the topical pharmaceutical composition is devoidor substantially devoid of a lipid. In one embodiment, thepharmaceutical composition is devoid of a lipid. In a furtherembodiment, the pharmaceutical composition is substantially devoid of alipid.

Methods of Treatment

According to an embodiment, the invention provides a method of treatinga disease, disorder or condition of the skin, the method comprisingadministering to a subject in need thereof, a topical pharmaceuticalcomposition comprising an antibacterial agent, a polymer, water and lessthan about 40% volatile solvent.

In a particular embodiment, the disease, disorder or condition of theskin is caused by a bacterial infection.

Exemplary bacterial infections include, but are not limited to,infections caused by Gram-positive and Gram-negative bacteria andmycoplasmas, including for example, Staphylococcus aureus,Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcushominis, Staphylococcus sapropphyticus, Streptococcus pyogenes,Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcusmutans, Streptococcus sanguis, Streptococcus faecium, Streptococcusfaecalis, Corynebacterium hofmannii, Bacillus subtilis, Neisseriameningitides, Neisseria gonorrhoeae, Haemophilus influenzae, Pasteurellamultocida, Branhamella catarrhalis, Proteus vulgaris, Propionibacteriumacnes, Enterobacter cloacae, Peptostreptococcus anaerobius, Clostridiumsporogenes, Clostridium difficile, Moraxella catarrhalis, Mycoplasmapneumoniae and Mycoplasma gallisepticum.

Suitably, the bacterial infection is an infection caused byStaphylococcus aureus.

In an embodiment, the disease, disorder or condition of the skin causedby a bacterial infection is acne, impetigo, superficially infecteddermatoses, wounds which have become infected, rosacea or folliculitis.

In one embodiment, the disease, disorder or condition of the skin isacne. In another embodiment, the disease, disorder or condition of theskin is impetigo.

In a further embodiment, the present compositions may be used as part ofa regimen for the treatment or prevention of a disease, disorder orcondition of the skin. In particular, the present compositions may beused in combination with a separate pharmaceutical dosage form.According to an embodiment, the separate pharmaceutical dosage form isan oral preparation. In one embodiment, the oral preparation is acapsule or tablet comprising an antibacterial agent.

DEFINITIONS

The phrases an “effective amount”, “an amount effective to” or a“therapeutically effective amount” are used herein to refer to an amountof the composition sufficient to have a therapeutic effect uponadministration. Effective amounts will vary with the particularcondition or conditions being treated, the severity of the condition,the duration of the treatment, and the specific components of thecomposition.

The terms “administering” and “administration” are used herein to meanany method which in sound medical practice delivers the composition to asubject in such a manner as to provide the desired therapeutic effect.

The terms “treatment” or “treating” of a skin disease, disorder orcondition encompasses alleviation of at least one symptom thereof, areduction in the severity thereof, or the delay, prevention orinhibition of the progression thereof. Treatment need not mean that thedisorder is totally cured. A useful composition herein need only toreduce the severity of the disorder, reduce the severity of symptomsassociated therewith, provide improvement to a patient's quality oflife, or delay, prevent or inhibit the onset of the disorder.

The term “lipid” is a generic term to describe fats and oils, such asfatty acids, esters of fatty acids, esters of glycerin, fatty alcohols,waxes, unsaponifiables, sterols, siloxanes, silanes, lanolin,hydrocarbons, glyceryl esters, essential oils, vegetable oils, mineraloils, animal oils and edible oils.

The term “salt thereof” refers to salts that are pharmaceuticallyacceptable. Such salts include: (1) acid addition salts, formed withacids such as, for example, acetic acid, benzoic acid, citric acid,gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloricacid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid,phosphoric acid, propionic acid, sorbic acid, succinic acid, sulfuricacid, tartaric acid, naturally and synthetically derived amino acids,and mixtures thereof; or (2) salts formed when an acidic proton presentin the parent compound is either (i) replaced by a metal ion e.g. analkali metal ion, an alkaline earth metal ion or an aluminium ion; or(ii) protonates an organic base such as, for example, ethanolamine,diethanolamine, triethanolamine, tromethamine and N-methylglucamine.

Any concentration range, percentage range or ratio range recited hereinis to be understood to include concentrations, percentages or ratios ofany integer within that range and fractions thereof, such as one tenthand one hundredth of an integer, unless otherwise indicated.

It should be understood that the terms “a” and “an” as used herein referto “one or more” of the enumerated components. It will be clear to oneof ordinary skill in the art that the use of the singular includes theplural unless specifically stated otherwise. Therefore, the terms “a,”“an” and “at least one” are used interchangeably in this application.

Throughout the application, descriptions of various embodiments use“comprising” language, however in some specific instances, an embodimentcan alternatively be described using the language “consistingessentially of” or “consisting of”.

All numbers expressing quantities, percentages or proportions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”

“Substantially devoid” of a specified component refers to a compositionwith less than about 1% by weight of the specified component. “Devoid”of a specified component refers to a composition where the specifiedcomponent is absent.

Other terms used herein are intended to be defined by their well knownmeanings in the art.

EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

The following compositions of Examples 1 and 2 may be prepared by themethods of preparation as set forth below in Example 4.

Example 1 Calcium Mupirocin Polymeric Composition

Item Ingredient % by weight 1 PVP/VA 30:70 10 2 Ethanol 10 3 Water 59.54 Hexylene glycol 20 5 Calcium mupirocin 0.5 Total 100

Example 2 Mupirocin Polymeric Composition

Item Ingredient % by weight 1 PVP/VA 30:70 10 2 Ethanol 10 3 Water 55.74 Hexylene glycol 23.8 5 Mupirocin 0.5 Total 100

Example 3 Additional Polymeric Compositions

The following placebo compositions were also prepared. Each compositionwas a clear solution. The mupirocin calcium or mupirocin may be added tothe placebo composition to form the final composition. A number of thecompositions prepared were devoid of co-solvent (i.e. devoid of hexyleneglycol), but yet were still a clear solution.

Item Ingredient % % % % % % % % % % 1 PVP/VA 11.9 12 4 10.2 10.3 3.210.7 20.9 49.1 49.8 30:70 2 Ethanol 23.4 24.5 23 21 20.7 23.8 4.7 5.517.9 18.9 3 Water 64.7 63.5 73 66.2 66.9 73 65.6 56.3 31.1 31.3 4Hexylene 0 0 0 2.6 2.1 0 19 17.3 1.9 0 glycol Total 100 100 100 100 100100 100 100 100 100

Example 4 Methods of Preparation Preparation of Calcium Mupirocin andMupirocin Compositions Using PVP/VA (30:70)

PVP/VA (30:70) is available as a 50% mixture in ethanol (Luviskol® VA37E, BASF). PVP/VA (30:70) as an ethanol solution was added to water anda turbid solution formed. Hexylene glycol was subsequently added to forma transparent solution. Calcium mupirocin or mupirocin was added anddissolved by vigorously shaking and rotating the preparation for 60minutes (in accordance with Examples 1 and 2 respectively).

Preparation of a Calcium Mupirocin Composition Using PVP/VA (60:40 and70:30)

Calcium mupirocin was dissolved in water followed by addition of anethanolic solution of PVP/VA (70:30) (Luviskol® VA 73E, BASF). Atransparent solution resulted. Hexylene glycol was not required.

Similarly, calcium mupirocin was dissolved in water, followed by theaddition of ethanol, and then PVP/VA (60:40) powder (Plasdon S630, ISPCorp.) was added. A transparent solution resulted. Hexylene glycol wasnot required.

Preparation of Placebos Using PVP/VA (30:70)

An ethanolic solution of PVP/VA (30:70) was applied to a polypropylenesheet and dried in an oven at 800° C. until the ethanol had evaporatedso as to afford a dried power. The dried PVP/VA powder was dissolved inethanol to form a transparent solution, followed by addition of water.Addition of water was carefully monitored to observe the transformationfrom a transparent solution into a turbid mixture. Where a turbidmixture resulted, hexylene glycol was added dropwise until a transparentsolution was obtained. The use of PVP/VA (30:70) powder rather than anethanolic solution of the polymer, afforded a number of compositionswhere the polymer could be solubilised in low levels of ethanol, yet bedevoid of hexylene glycol.

Example 5 Polymeric Compositions

The following compositions (Examples 5a-5f) further exemplify thepresent invention.

Example 5a Co-Solvent Free/Low Ethanol Calcium Mupirocin PolymericSolution

Item Ingredient % by weight 1 PVP/VA 30:70 48 2 Ethanol 19 3 Water 31 4Calcium mupirocin 2 Total 100

Example 5b Co-Solvent Free/Low Ethanol Calcium Mupirocin Polymeric Gel

Item Ingredient % by weight 1 PVP/VA 30:70 47 2 Ethanol 19 3 Water 31 4Xanthan gum 1 5 Calcium mupirocin 2 Total 100

Example 5c Co-Solvent Free/Low Ethanol Clindamycin Phosphate PolymericGel

Item Ingredient % by weight 1 PVP/VA 30:70 25 2 Ethanol 10 3 Water 62.754 Xanthan gum 1 5 Clindamycin phosphate 1.25 Total 100

Example 5d Co-Solvent Free/Low Ethanol Metronidazole Polymeric Gel

Item Ingredient % by weight 1 PVP/VA 30:70 25 2 Ethanol 10 3 Water 63 4Xanthan gum 1 5 Metronidazole 1 Total 100

Example 5e Calcium Mupirocin in Combination with (1) Mupirocin, (2)Clotrimazole, (3) Hyaluronic Acid and (4) Clobetasol Propionate

(1) (2) (3) (4) Ingredient % by weight % by weight % by weight % byweight PVP/VA  10  50  50  50 30:70     Ethanol  10  19  19  19 Water 58  28  27  28.95 Hexylene  20  0  0  0 glycol Actives  1% mupirocin Ca 2% mupirocin Ca  2% mupirocin Ca  2% mupirocin Ca  1% mupirocin  1%clotrimazole  2% hyaluronic acid  0.05% clobetasol propionate Total 100100 100 100

Example 5f Calcium Mupirocin in Combination with (5) Tretinoin, (6)Hydrocortisone, (7) Adapalene and (8) Metronidazole

(5) (6) (7) (8) Ingredient % by weight % by weight % by weight % byweight PVP/VA  50  50  50  50 30:70 Ethanol  19  19  19  19 Water 28.975  28  28.9  28.5 Hexylene  0  0  0  0 glycol Actives  2%mupirocin Ca  2% mupirocin Ca  2% mupirocin Ca  2% mupirocin Ca  0.025%tretinoin  1% hydrocortisone  0.1% adapalene  0.5% metronidazole Total100 100 100

Example 6 Drug Release

The following formulations were also prepared and used to assess drugrelease from the compositions of the present invention.

Ingredient % by weight % by weight % by weight PVP/VA (70:30) (60:40)(30:70) 10 10 10 Ethanol 10 10 10 Water 79.5 78 59.5 Hexylene glycol 0 020 Calcium mupirocin 0.5 2 0.5 Total 100 100 100

Methodology: Franz Cell Drug Release Studies

In vitro drug release experiments were carried out using a Franz cellmethodology (Fan et al. (2004) J. Contr. Rel. 98, 355-365).

A Franz cell apparatus was used (Permegear, USA) with 12 mL 0.01 M PBSsolution, pH 7.4 (Aldrich) in the Franz cell receptor compartment andthe donor compartment. Two hydrophilic Durapore™ polyvinylidene fluoridemembranes (Millipore) were placed between the receptor and donorcompartments (25 mm diameter, 0.1 μm pore size with 70% porosity, 125 μmthickness). The temperature of the Franz cells was optimized andmaintained at 30° C.

About 30-50 mg of each formulation was placed on the membranes from thedonor compartment. 200 μL aliquots of the receptor phase were drawn atcertain time intervals and subjected to HPLC analysis for drug content.Each aliquot was replaced by an equivalent amount of PBS solution.

HPLC Analysis

Methanol:H₂O (50:50) was used as the diluent for the HPLC samplepreparations. A reversed phase HPLC analytical method was used, with anApollo C₁₈ column (150×4.6 mm, 5 μm), Photodiode array detector (210-300nm range, detection at 223 nm), with isocratic elution at 1.5 mL/min anda mobile phase containing 55% methanol and 45% 0.1 M ammonium acetatebuffer (pH 5.7). The retention time of calcium mupirocin was about 6minutes and the total run time was 10 minutes. The error of analysis inthe HPLC analyses was found to be 2-5%. Standard deviation (SD) and %relative standard deviation (% RSD) were found to be in the range of1-7% and about 20%, respectively.

Results and Discussion

In an attempt to prepare a homogeneous topical composition comprisingcalcium mupirocin where the rate of release of the active is modulated,a number of polymers (Eudragit E100, Eudragit S100, Eudragit NE30D andEudragit RLPO) were explored, but these polymers generally precipitatedfrom the composition.

Desirably, PVP/VA was shown to be able to modulate release of the activeagent, but remain solubilized in the composition. In particular, PVP/VAwith varying ratios of PVP:VA monomers were explored, namely 70:30,60:40 and 30:70. It was observed that PVP/VA 60:40 and 70:30 weresoluble in compositions comprising 10% ethanol. However PVP/VA 30:70 wasnot soluble and required the addition of 20% hexylene glycol tosolubilize the copolymer. It was later demonstrated, however, that acomposition comprising PVP/VA 30:70 but devoid of hexylene glycol couldbe prepared by using PVP/VA 30:70 polymer powder, rather than as anethanolic solution of the polymer. The PVP/VA 30:70 as a powder, ratherthan an ethanolic solution, afforded greater control over the relativeconcentrations of polymer, ethanol and water present in the composition.

Modulation in the rate of release of calcium mupirocin is illustrated inFIG. 1. This figure shows that for the composition comprising PVP:VA30:70, calcium mupirocin release reached equilibrium after 4 hours. Thiscompares to only 2 hours for the PVP:VA formulations having 60:40 and70:30 ratios. This demonstrates a more gradual release of active agentwhere the ratio of the hydrophobic monomer (VA) is greater than theratio of the hydrophilic monomer (PVP), i.e. as is the case for PCP/VA30:70.

FIG. 2 illustrates the first order derivative of the release data. Thesedata show a clear difference in the release profile of PVP/VA 30:70copolymer (on the one hand) and PVP:VA 60:40 and PVP:VA 70:30.

FIG. 3 illustrates that as the PVP/VA ratio changes from 70:30 to 60:40to 30:70 (increasing hydrophobicity), wherein the release exponent (n)increases from 0.17 for PVP:VA 70:30 to 0.47 for PVP:VA (60:40) and 0.41for PVP:VA (30:70). Furthermore, the rate constant (k) is reduced from0.3 min⁻¹ (for PVP:VA 70:30) to 0.08 min⁻¹ (for both PVP:VA 60:40 andPVP:VA 30:70).

Thus, the n and k values are affected by changes in the hydrophobicityof the respective PVP/VA copolymers.

Example 7 Rub Resistance and Water Resistance

The following placebo formulations were to assess the water- andrub-resistance of the compositions of the present invention.

Ingredient % by weight % by weight % by weight % by weight Polymer 1011.9 12 11 (PVP/VA) Ethanol 10 23.4 24.5 20 Water 60 64.7 63.5 69Hexylene glycol 20 0 0 0 Total 100 100 100 100

Methodology

Rub Resistance Studies

Around 20 mg of each formulation was spread evenly on separate glassslides. The slides were dried at 45° C. for 3 hours. Each film wassubjected to abrasion with a 100 gm standard weight covered with a lintfree tissue (Kimwipes™, Kimberley-Clark). In particular, the 100 gmstandard weight covered with a lint free tissue was slowly oscillated 20times back and forth over each dried film. The weight of the glassslides with the dried films before and after the abrasion was measuredto evaluate the rub-resistance of each film.

Water Resistance Studies

Transpore™ medical tape (3M) was affixed to glass slides. Around 200 mgof each formulation was spread evenly on the medical tape. The slideswere then dried at 45° C. for 3 hours. The weight of each dried platewas noted. The dried plates were subsequently immersed in water at 45°C. for 30 minutes. The plates were removed from the water and dried.Again, the weight of each slide was noted.

The difference in the weight of each slide (i.e. before and after beingimmersed in water) was calculated and represented the wash resistance ofthe polymeric films.

Results and Discussion

FIG. 4( a) illustrates that the addition of hexylene glycol does notimpact the rub resistance of the compositions.

FIG. 4( b) illustrates that good wash resistance may be obtained withcompositions comprising low amounts of ethanol e.g. about 20%.

FIG. 4( c) illustrates that the addition of hexylene glycol negativelyimpacts the wash resistance of the compositions of the invention.

These data demonstrate that a composition with about 20% ethanol, andfree of hexylene glycol, will have both adequate water and rubresistance. It was also observed that the compositions without hexyleneglycol dried down more rapidly, and result in a cosmetically elegantfilm (i.e. without the stickiness or tackiness associated with hexyleneglycol).

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

1. A topical pharmaceutical composition comprising a therapeuticallyeffective amount of an antibacterial agent, a polymer, water, less thanabout 40% w/w of at least one volatile solvent, and optionally one ormore dermatologically acceptable excipients.
 2. The compositionaccording to claim 1 wherein the antibacterial agent is mupirocin,gentamicin, neomycin, streptomycin, cefpodoxime proxetil, clindamycin,lincomycin, erythromycin, bacitracin, gramicidin(s), vancomycin,doxycycline, minocycline, oxytetracycline, tetracycline, fosfomycin,fusidic acid, sulfacetamide, metronidazole, benzoyl peroxide anddapsone, pharmaceutically acceptable salts thereof, and mixturesthereof.
 3. The composition according to claim 2 wherein theantibacterial agent is present in an amount from about 0.1% to about 10%by weight.
 4. The composition according to claim 1 wherein the at leastone volatile solvent is selected from ethanol, propanol, iso-propanol,n-butyl alcohol, t-butyl alcohol, butoxy ethanol, acetone, ethyl acetateor butyl acetate.
 5. The composition according to claim 4 wherein the atleast one volatile solvent present in the composition is ethanol.
 6. Thecomposition according to claim 5 wherein the volatile solvent is amixture of at least two volatile solvents, and wherein the firstvolatile solvent is ethanol.
 7. The composition according to claim 6wherein the volatile solvent is a mixture of ethanol and iso-propanol.8. The composition according to claim 6 wherein the volatile solvent isa mixture of ethanol and ethyl acetate.
 9. The composition according toclaim 1 wherein the topical pharmaceutical composition further comprisesa second pharmaceutically acceptable active agent.
 10. The compositionaccording to claim 9 wherein the second pharmaceutically acceptableactive agent is selected from the group consisting of a secondantibacterial agent, a retinoid, a corticosteroid, an antifungal agent,a skin conditioning agent, a nutritional agent, or an antiseptic agent.11. The composition according to claim 1 wherein the one or moredermatologically acceptable excipients are selected from the groupconsisting of at least one co-solvent, a pH adjusting agent, ahumectant, a film extender, a chelating agent, an antioxidant, apreservative, a gelling agent, a fragrance, a colorant, a penetrationenhancer, and a combination or mixture thereof.
 12. The compositionaccording to claim 11 wherein the at least one co-solvent is selectedfrom an alcohol, a carboxylic acid, a diol, a polyol or a combination ormixture thereof, present in an amount from about 1% to about 30% byweight.
 13. The composition according to claim 12 wherein the alcohol isselected from amyl alcohol, benzyl alcohol, cyclohexanedimethanol,diacetone alcohol, hexyl alcohol, or tetrahydrofurfuryl alcohol; and thediol is selected from 1,2-hexanediol, butylene glycol, diethyleneglycol, dipropylene glycol, ethyl hexanediol, ethylene glycol, hexyleneglycol, pentylene glycol, propylene glycol, tetraethylene glycol,triethylene glycol, or tripropylene glycol; and the polyol is selectedfrom polyethylene glycol, butanetriol, glycerol and 1,2,6-hexanetriol.14. The composition according to claim 11 wherein the at least oneco-solvent is propylene glycol, the co-solvent is a mixture of at leasttwo co-solvents which are polyethylene glycol and propylene glycol. 15.The composition according to claim 1 which comprises a volatile solventpresent in an amount from about 10% to about 25% by weight and whichcomposition is substantially devoid or devoid of a co-solvent.
 16. Atopical pharmaceutical composition comprising: (a) calcium mupirocin,(b) a PVP/VA co-polymer in an amount from about 30% to about 60% byweight, (c) water in an amount from about 20% to about 40% by weight,and (d) a volatile solvent in an amount from about 10% to about 25% byweight; and optionally a gelling agent, and other dermatologicallyacceptable excipients thereof.
 17. The composition according to claim 16wherein the ratio of PVP monomer to VA monomer in the PVP/VA is fromabout 30:70 to about 70:30.
 18. The composition according to claim 17wherein the PVP/VA is present in a ratio of about 30:70 and wherein thecomposition is free of hexylene glycol.
 19. A method of treating abacterial infection of the skin in a mammal in need thereof, comprisingadministering to said mammal, a topical pharmaceutical compositionaccording to claim
 1. 20. The method according to claim 19 wherein thebacterial infection of the skin is acne, impetigo, superficiallyinfected dermatoses, wounds which have become infected, rosacea orfolliculitis.
 21. A method of treating a bacterial infection of the skinin a mammal in need thereof, comprising administering to said mammal, atopical pharmaceutical composition according to claim
 16. 22. The methodaccording to claim 21 wherein the bacterial infection of the skin isacne, impetigo, superficially infected dermatoses, wounds which havebecome infected, rosacea or folliculitis.